Bone marrow transplantation, BMT, is indicated following a process which destroys bone marrow. For example, following intensive systemic radiation or chemotherapy, bone marrow is the first target to fail. Metastatic cancers are commonly treated with very intensive chemotherapy, which is intended to destroy the cancer, but also effectively destroys the bone marrow. This induces a need for BMT. Leukemia is a bone marrow malignancy, which is often treated with BMT after chemotherapy and/or radiation has been utilized to eradicate malignant cells. BMT is currently used for treatment of leukemias which are life-threatening. Some autoimmune diseases may be severe enough to require obliteration of their native immune systems which includes concomitant bone marrow obliteration and requires subsequent bone marrow transplantation. Alleviation of any but the most acute life-threatening conditions involving bone marrow disorders with BMT is, however, generally regarded as too risky, because of the likelihood of the onset of graft versus host disease.
Graft-versus-host disease, GVHD, is an immunological disorder that is the major factor that limits the success and availability of allogeneic bone marrow or stem cell transplantation (collective referred to herein as allo-BMT) for treating some forms of otherwise incurable hematological malignancies, such as leukemia. GVHD is a systemic inflammatory reaction which causes chronic illness and may lead to death of the host mammal. At present, allogeneic transplants invariably run a severe risk of associated GVHD, even where the donor has a high degree of histocompatibility with the host.
GVHD is caused by donor T-cells reacting against systemically distributed incompatible host antigens, causing powerful inflammation. In GVHD, mature donor T-cells that recognize differences between donor and host become systemically activated. Current methods to prevent and treat GVHD involve administration of drugs such as cyclosporin-A and corticosteroids. These have serious side effects, must be given for prolonged periods of time, and are expensive to administer and to monitor. Attempts have also been made to use T-cell depletion to prevent GVHD, but this requires sophisticated and expensive facilities and expertise. Too great a degree of T-cell depletion leads to serious problems of failure of engraftment of bone marrow stem cells, failure of hematopoietic reconstitution, infections, or relapse. More limited T-cell depletion leaves behind cells that are still competent to initiate GVHD. As a result, current methods of treating GVHD are only successful in limited donor and host combinations, so that many patients cannot be offered potentially life-saving treatment.